'Aw 464' diaporamas de présentation

Quinols - Discovery Program

Quinols - Discovery Program. Initiated 1998 - novel structures via oxidation of interesting phenols Rigorous antitumour profiling of resulting new chemical entities Lead compounds identified from 2 novel chemical series (AW 464, AJM 290). In Vitro Antitumour Activity.

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2 lead compounds identified from 2 novel chemical series:- AW 464 (1 st series)

2 lead compounds identified from 2 novel chemical series:- AW 464 (1 st series) AJM 290 (2 nd series) Potent, selective in vitro and in vivo activity: renal, colon, breast, melanoma cell lines Evidence suggests activity associated with inhibition of HIF signalling

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IL-1 β alone

Inhibition of HIF signal transduction A) Inhibition of HRE-HIF-1 α DNA binding. Dose-dependent down-regulation of hypoxia-induced gene transactivation (BNIP3 mRNA) by B) AW 464 C) AJM 290 and D) protein (CA-IX, BNIP3) expression. D. A.

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Antitumour Quinols as Novel Inhibitors of Thioredoxin Signalling

? 10% Tween/PBS ? 200 mg/kg i.p. d 8 ? 50 mg/kg i.p.d 8-12. Proposed quinol-thioredoxin binding geometry. Cell cycle perturbation by Quinols. NCI mean LC 50 graphs: AW 464 BW 114. Con. 24 h. G1/0. S. G2/M. } Colon. Cell Number. Inhibition of Tx/TR signalling:

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AW 464 induced ASK-1/Trx dissociation and JNK activation in HCT116 cells.

whole cell lysates. IP: Trx. ? p54. ? p54. phospho-JNK. ? p46. ? p46. ? ASK-1. total JNK. ? Trx. DMSO 1. DMSO 1. DMSO 2. DMSO 2. 5 m M AJM 290. 5 m M AJM 290. 5 m M AW 464. 5 m M AW 464. actin. DMSO 0.5 1 5 10.

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